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Semagacestat is an inhibitor of the γ-secretase complex. It causes a reduction in the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium. Semagacestat increases β-CTF in cell lysates, and the increase can be attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. Semagacestat causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine Aβ42 formation in CTX is roughly 12-fold less than Aβ40 in accordance with data for neurons from wild type mice.
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